Background:Hyperandrogenism during childhood is a key feature of several pediatric endocrine disorders, including premature adrenarche and polycystic ovary syndrome (PCOS). The adrenal gland contributes significantly to circulating androgens, yet the regulation of adrenal steroidogenic enzymes during the prepubertal period remains poorly understood. This study aimed to investigate adrenal androgen synthesis in a prepubertal rat model of ovarian removal and identify key enzymes responsible for hyperandrogenism. Methods:Female Sprague-Dawley rats underwent either ovariectomy or sham surgery on postnatal day (PND) 15. Serum steroid hormone levels were measured by enzyme-linked immunosorbent assay (ELISA). Adrenal tissue was analyzed by RNA sequencing to screen for differentially expressed genes (DEGs) involved in steroidogenesis; findings were subsequently validated by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunohistochemistry (IHC). The functional role of a candidate gene in steroid synthesis was assessed through in vitro overexpression and in vivo pharmacological inhibition. Results:Serum testosterone levels increased on PND 25 and 30 after ovariectomy, whereas dehydroepiandrosterone (DHEA) concentrations decreased. Transcriptomic analysis revealed that adrenal AKR1C3 was the most significantly DEG between OVX and sham-operated controls. Its expression was elevated in OVX rats from PND 25 to PND 30, as confirmed by qPCR, western blot, and IHC. In vitro, AKR1C3 overexpression converted exogenous androstenedione to testosterone. Conversely, in vivo administration of the AKR1C3 inhibitor ASP9521 (2 mg/kg.day) to OVX rats reduced serum testosterone levels. Additionally, adrenal expression of CYP17A1, another key enzyme in androgen biosynthesis, was also increased in OVX rats from PND 25 to 30. Conclusions:This study demonstrates that prepubertal ovarian removal upregulates adrenal AKR1C3 and CYP17A1, leading to enhanced adrenal androgen synthesis and systemic hyperandrogenism. These findings provide mechanistic insights into adrenal-derived hyperandrogenism with potential clinical implications for pediatric endocrine disorders such as premature adrenarche and PCOS.

Reactive oxygen species (ROS)-induced gut microbiota dysbiosis is a pivotal driver of intestinal inflammation. Clinical data mining reveals that patients with inflammatory bowel disease (IBD) exhibit elevated oxidative stress and decreased SOD2 expression, both correlating strongly with inflammatory onset. Based on these findings, we engineered an oral probiotic strain, KI@lSodA, derived from Lactococcus lactis NZ9000, to constitutively express its superoxide dismutase (SodA) for the treatment of intestinal inflammation. In murine models of DSS-induced enteritis, oral administration of KI@lSodA significantly attenuated intestinal inflammation and repaired epithelial barrier damage under both acute and chronic conditions. Mechanistically, the engineered Lactococcus restored gut microbial homeostasis by increasing beneficial commensal bacteria and suppressing the infiltration of phagocytes, including neutrophils and macrophages. By modulating the innate and adaptive immune landscapes, this approach offers a potential strategy for treating IBD and preventing disease progression through the targeted restoration of redox balance and gut microbiota health.

PURPOSE:Approximately 85-90% patients with small for gestational age (SGA) experience catch-up growth (CUG) by the age of 2, with their height reaching - 2 standard deviation scores (SDS) or 3% of the height of children of the same age and sex. However, SGA patients with CUG (CUG-SGA) tend to be at a higher risk of developing insulin resistance, obesity, metabolic syndrome, and cardiovascular diseases. This study explored the metabolic conditions of CUG-SGA patients in East China and analyzes the risk factors that may contribute to metabolic issues. METHODS:This multi-center study in East China involved 151 SGA patients aged 2-8 years. Patients were categorized into two groups: CUG-SGA (height not below - 2 SDS among the children of the same age and gender) and NCUG-SGA (SGA patients without CUG, height below - 2 SDS among the children of the same age and gender). Tests for insulin-like growth factor 1 (IGF-1), blood glucose (BG), insulin (INS), triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and leptin (LEP) were conducted after a 12-hour fast. Body mass index (BMI) and homeostatic model assessment for insulin resistance (HOMA-IR) were calculated. RESULTS:(1) Out of 151 SGA patients, 82 were girls and 69 were boys. There were 85 patients in CUG-SGA group, including 38 girls and 47 boys. There were 66 patients in NCUG-SGA group, including 44 girls and 22 boys. The height SDS (H-SDS) and weight SDS (W-SDS) of CUG-SGA group were significantly higher than those of NCUG-SGA group (P < 0.05). (2) The level of IGF-1 SDS, ALT, and GGT in the CUG-SGA group were significantly higher than those in the NCUG-SGA group (P < 0.01). The level of W-SDS, LEP, INS, and HOMA-IR in the CUG-SGA group are significantly higher than those of the NCUG-SGA group (P < 0.05). (3) Correlation analysis in SGA patients indicated positive correlations between BG and W-SDS, LEP, and GGT (P < 0.05). INS was positively correlated with IGF-1 SDS, GGT (P < 0.01), and W-SDS (P < 0.05). HOMA-IR was positively correlated with IGF-1 SDS (P < 0.01). TC was positively correlated with LEP (P < 0.05), and TG was negatively correlated with IGF-1 SDS (P < 0.01). (4) After further controlling for confounding factors and performing multiple regression analyses, the results showed that BMI-SDS had a significant positive effect on INS and a significant negative effect on HOMA-IR. IGF-1 had a significant positive effect on INS and HOMA-IR, and a significant negative effect on TG. LEP had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. ALT had a significant negative effect on INS and HOMA-IR, and a significant positive effect on TC and TG. GGT had a significant positive effect on BG, INS, HOMA-IR, TC, and TG. CONCLUSION:(1) IGF-1 SDS was significantly positively correlated with fasting INS (FINS) and HOMA-IR, and exerted a significant positive effect on fasting BG. If IGF-1 levels in CUG-SGA infants remain persistently high, careful monitoring of changes in glucose metabolism is warranted. (2) CUG-SGA patients had higher LEP resistance compared to NCUG-SGA patients, potentially contributing to future metabolic issues. (3) Elevated ALT and GGT levels in SGA patients may warrant close monitoring of glucose metabolism, particularly in CUG-SGA patients.

OBJECTIVES:To explore the application of the colloidal gold method and chemiluminescence method in detecting gonadotropin (Gn) in morning urine for assessing pubertal development status in children. METHODS:A total of 132 children diagnosed with central precocious puberty (CPP), early and fast puberty (EFP), and premature thelarche (PT) at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from November 2021 to December 2022 were included, along with 685 healthy children who underwent routine health examinations at the hospital's pediatric health care department during the same period. All 132 patients underwent a gonadotropin-releasing hormone (GnRH) stimulation test. Both patients and healthy children had their urinary Gn levels measured using the colloidal gold method and chemiluminescence method, including levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The correlation between serum Gn and urinary Gn detected by the two methods, as well as the correlation between Tanner stages of healthy children and urinary Gn, was analyzed. RESULTS:Urine Gn levels detected by both the colloidal gold method and chemiluminescence method showed a positive correlation with serum LH baseline values, LH peak values, baseline LH/FSH ratios, and peak LH/FSH ratios (P<0.05). In healthy children, urinary LH levels detected by the chemiluminescence method gradually increased from Tanner stage Ⅰ to Ⅳ (P<0.05), while urinary FSH levels were lower in Tanner stage I than in stages Ⅱ, Ⅲ, and IV (P<0.05). Urinary LH levels detected by the colloidal gold method were lower in Tanner stage I compared to stages Ⅱ, Ⅲ, and IV, with the highest levels observed in Tanner stage Ⅳ (P<0.05). Additionally, urinary FSH levels in Tanner stage Ⅲ were higher than in stages Ⅰ and Ⅱ (P<0.05). The area under the receiver operating characteristic curve for evaluating Tanner stages I and II in healthy children using urinary LH and FSH levels by the chemiluminescence method and urinary LH levels by the colloidal gold method were 0.730, 0.699, and 0.783, respectively. CONCLUSIONS:The colloidal gold method and chemiluminescence method for detecting Gn in morning urine show good correlation with serum Gn levels. As a non-invasive and convenient detection method, the colloidal gold method can serve as a useful tool for screening the onset of pubertal development in children.

Platelets are hypothesized to participate in the pathogenesis of Crohn’s disease (CD) by interacting with other inflammatory cells such as natural killer (NK) cells. In this study, we aimed to evaluate the effects of platelet—NK cell interactions, both in vitro and in vivo, along with the corresponding mechanisms. Clinical data were collected from patients with CD and IL-10 receptor alpha (IL-10RA) mutations, with the control group being comprised of patients with functional abdominal pain. Platelets and NK cells from the patients’ colon tissues were immunostained. Dextran sulfate sodium (DSS)-induced colitis models using wild type (WT) and Stimulator of Interferon Genes knockout (STING−/−) mice were evaluated. Both purified CD41+ and CD41−NK cells were cultured with IL-2 and STING inhibitor C-176 to determine in vitro cell proliferation and Type 3 (T3) cytokine expression. Flow cytometry, enzyme-linked immunosorbent assays, and RT-PCR were used to assess the expression of CD41, IL-17, and adhesion-related molecules in mouse and human NK cells. Circulating and intestinal platelets were higher in patients with IL-10RA mutations compared to CD patients and correlated positively with serum cytokines, fecal calprotectin (FCP), and blood NK cells. Gut inflammation and T3 cytokine expression in NK cells were significantly lower in STING−/− mice compared to WT mice. Platelet-adherent NK cells showed significant proliferation and enhanced T3 cytokine expression, whereas STING inhibition markedly suppressed platelet adhesion, cell proliferation, and T3 cytokine expression. The naïve lung tissue of mice also displayed similar platelet-NK cell interactions. Platelet adhesion on NK cells led to higher CD24 expression compared to CD41−NK cells and we observed relatively higher CD24 in the NK cells from patients with IL-10RA mutations compared to patients with CD. Spontaneous platelet adhesion via STING signaling potentiates NK cell proinflammatory response in CD.

Objective:To assess the therapeutic effects of gonadotropin-releasing hormone agonist (GnRHa) on children with familial central precocious puberty (FCPP) due to Makorin ring finger Protein 3 (MKRN3) gene mutations. Methods:Children with central precocious puberty (CPP) who were admitted to the Pediatric Endocrinology Department of Shanghai Ruijin Hospital from 2014 to 2021 were enrolled, of whom 4 FCPP children with MKRN3 gene mutations, including 3 girls and 1 boy, were selected as research subjects. Their height, weight, body mass index (BMI), predicted adult height (PAH), bone age, bone age advance (BAA, bone age minus chronological age), height-based standard deviation scores (Ht-SDS) corresponding to the chronological age, concentrations of sex hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), and development of sexual organs were compared before and after at least 2 years of GnRHa treatment. Results:After at least 2-year GnRHa treatment, mean volume of uterus of three girls decreased from 5.72 ± 2.58 to 2.12 ± 1.62 mL (p < 0.05) and mean volume of ovaries decreased from 3.61 ± 1.67 to 0.62 ± 0.22 mL (p < 0.05) as well, indicating that the gonadal development was effectively inhibited. Basal concentrations of LH and FSH in serum decreased, indicating that the secretion of gonadotropin in the anterior pituitary is inhibited. BAA and Ht-SDS decreased, suggesting that the bone age was restrained, and the growth rate was slowed down to some extent. Both average BMI and obesity prevalence (X 2 = 7.188, p=0.029) decreased during the treatment. No obvious adverse reaction was found. Conclusion:Long-term GnRHa treatment could effectively inhibit the gonadal development and FSH secretion in FCPP children with MKRN3 gene mutations, while this inhibitory effect on the bone age and growth rate was not obvious. Adverse reactions such as increased prevalence of obesity were not found. A large-scale, long-term follow-up study is required to indicate whether patients' final height (FH) could reach PAH or target height (TH).

Objective: This study aims to investigate the clinical phenotypic characteristics of acrodysostosis1 (ACRDYS1) caused by PRKAR1A gene mutations, and discuss the correlation between genotype and phenotype by reviewing literatures. Methods: The clinical data of a 13-year-old male child with skeletal dysplasia and multiple hormone resistance was analyzed. The child's clinical exons were examined using second-generation target region capture high- throughput sequencing technology, and suspected mutated loci were verified in the parents through Sanger sequencing. Additionally, a literature review was conducted to analyze the relationship between clinical phenotypes and genotypes in other affected children. The treatment involved growth hormone (GH) for dwarfism and Chorionic Gonadotropin (HCG) for delayed sexual development. Results: The child presented with short stature (<= 3SD), low body mass (-1 similar to -2SD), facial bone abnormalities (wide face, wide eye spacing, maxillary hypoplasia, flattened nasal ridge, small and upturned nostrils), limb hypoplasia (stubby fingers and toes), and delayed puberty (13 years old with 1.5 ml testes and Tanner stage 1). Laboratory tests revealed resistance to parathyroid hormone and thyrotropin, complete growth hormone deficiency, and low testosterone. X-rays indicated skeletal hypoplasia of the extremities. Whole-exome sequencing identified a heterozygous missense mutation (c.524 A > G, p.A346T) in the PRKAR1A gene, which was classified as a pathogenic variant per ACMG. The child's clinical features confirmed ACRDYS1. A literature review showed a link between the PRKAR1A gene and the child's phenotype. The child initially presented with high Thyroid Stimulating Hormone (TSH) and was treated with levothyroxine, adjusted for normal thyroid hormone levels. Despite advanced bone age, severe short stature was addressed with GH therapy (0.16 IU/kg.d), increasing height by 9.6 cm in one year. The child also had small genitalia, treated with HCG, leading to significant enlargement. Conclusion: Clinicians should be attentive to whether children presenting with short stature, short fingers, and facial bone dysplasia also had comorbid hormonal resistance. Genetic testing can confirm the diagnosis of ACRDYS1. Remarkable results have been achieved in terms of height improvement through GH injections and sexual development enhancement through HCG injections. These findings suggested a new direction for studying the pathogenic mechanism of hormone resistance in ACRDYS1 children.

Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of WFS1, autosomal dominant or recessive inherited, are related to a broad clinical spectrum. Molecular genetic tests were performed, and clinical phenotypes of three WFS1-associated cases were evaluated. The expression of WFS1, viability, and endoplasmic reticulum (ER) stress of the MIN6 cell and structural analysis of the variant WFS1 protein were revealed. Furthermore, a total of 75 pathogenic WFS1 variants from ClinVar were included to analyze variant-phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in WFS1 of the 3 patients with early-onset diabetes, including c.613G >A (p.G205S), c.2053C >T (p.R685C), and c.169G >A (p.A57T). Decreased expression, reduced β-cell viability and enhanced ER stress were found in all variants. Protein stability and structural analysis showed increased protein stability and molecule flexibility of variants p.R685C in the ER-lumenal domain and p.A57T in the ATP6VIA-interaction region, while destabilized protein and rigidificated structure by p.G205S variant in the EF-hand domain at the cytoplasm region. Remarkably, topology was found an independent risk factor with urological symptoms (USs) (p=0.007, odds ratio [OR] 4.768 [95% confidence interval (CI): 1.531-14.854]). Surprisingly, variants in the cytoplasm had the highest risk with US than ones in the ER-lumenal domain (p=0.008, OR 22.013 [95% CI: 2.270-213.428]). The functional analysis of the three variants of uncertain significance in WFS1 indicated a quantitative and qualitative damage to wolframin with proven pathogenicity. The topology of the WFS1 protein may play an important role in the pathogenesis of β-cell and urological defects in WFS1-associated disease.

Background Crohn’s disease (CD) is a chronic inflammatory disorder characterised by intestinal dysbiosis. While inflammation-induced leakage of host proteins is a known phenomenon in CD, how these proteins affect the gut microbiota and contribute to dysbiosis remains unclear. One hypothesis is that commensal bacteria hijack these proteins, exacerbating inflammation in CD. Design To investigate host-microbiota interactions in CD, we measured fatty acid-binding protein 2 (FABP2) levels in patients with CD and in mouse models of dextran sulfate sodium induced enteritis and interleukin 10 knockout spontaneous enteritis. Proteomic approaches, including bacterial pull-down and mass spectrometry, were employed to identify commensal targets of FABP2. Functional studies were conducted using wild type and EF3041 -deficient Enterococcus faecalis strains, along with α-FABP2 antibody treatment, to assess their effects on intestinal inflammation and microbiota composition. Results FABP2 levels were elevated in plasma and faeces of patients with CD, as well as in the mouse models. This was accompanied by dysbiosis of gut commensal bacteria. E. faecalis hijacked luminal FABP2 to promote its proliferation via pheromone-binding protein EF3041, which activated quorum-sensing pathways. Deletion of EF3041 abolished this response, while complementation with EF3041 restored it. Injection of α-FABP2 antibody or transplantation of Δ EF3041 mutant strain significantly reduced epithelial damage, mitigated dysbiosis and alleviated inflammation and symptoms of enteritis in mice. Conclusion This study reveals a novel mechanism by which commensal bacteria use host-derived FABP2 to drive dysbiosis and worsen CD pathology. Targeting the FABP2-EF3041 axis may offer new diagnostic and therapeutic avenues for managing CD.

Background The clinical manifestations of nonclassical 11beta-hydroxylase deficiency are very similar to those of non-classical 21-hydroxylase deficiency. For this study, we investigated the relationship between the clinical and molecular features of congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency and reviewed the related literature, which are expected to provide assistance for the clinical diagnosis and analysis of congenital adrenal hyperplasia. Methods Clinical data for 10 Chinese patients diagnosed with congenital adrenal hyperplasia in our hospital from 2018 to 2022 were retrospectively analyzed. We examined the effects of gene mutations on protease activity and constructed three-dimensional structure prediction models of proteins. Results We describe 10 patients with 11beta-hydroxylase gene mutations ( n = 5, 46,XY; n = 5, 46,XX), with 10 novel mutations were reported. Female patients received treatment at an early stage, with an average age of 2.08 ± 1.66 years, whereas male patients received treatment significantly later, at an average age of 9.77 ± 3.62 years. The most common CYP11B1 pathogenic variant in the Chinese population was found to be c.1360C > T. All mutations lead to spatial conformational changes that affect protein stability. Conclusions Our study found that there was no significant correlation between each specific mutation and the severity of clinical manifestations. Different patients with the same gene pathogenic variant may have mild or severe clinical manifestations. The correlation between genotype and phenotype needs further study. Three-dimensional protein simulations may provide additional support for the physiopathological mechanism of genetic mutations.

Central precocious puberty (CPP) refers to a syndrome of early puberty initiation with a characteristic increase in the release of gonadotropin-releasing hormone (GnRH); therefore, it is also called GnRH-related precocious puberty. About a quarter of idiopathic central precocious puberty (ICPP) may be familial. Studies suggest that mutations of makorin ring finger protein 3 (MKRN3) can cause familial central precocious puberty (FCPP). In this report, we describe a Chinese female patient carrying a novel MKRN3 variant (c.980G>A/p.Arg327His) and presenting the CPP phenotype. This novel variant attenuated its own ubiquitination, degradation, and inhibition on the transcriptional and translational activity of GNRH1, which was verified through functional tests. We can consider this variant as a loss-of-function mutation, which subsides the inhibition of GnRH1-related signaling and gives rise to GnRH-related precocious puberty.

Enteric bacteria use up to 15 In Salmonella enterica, metabolic enzyme acetylation regulates carbon metabolism. Here, glucose availability is shown to regulate ammonium assimilation and virulence in Salmonella. Glucose regulates acetylation of glutamate and glutamine biosynthesis enzymes to enhance bacterial survival in infected mice.

WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout of Wnt5a and Wnt5b ( Wnt5 DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8 + T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences between Wnt5 DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8 + T cell GZMB expression in the Wnt5 DKO mice. In addition, neutrophils from the Wnt5 DKO colitic mice exert stronger suppression of CD8 + T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treated Wnt5 DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

Background Glucocorticoids (GCs) are commonly used to treat autoimmune diseases and malignancies in children and adolescents. Growth retardation is a common adverse effect of GC treatment in pediatric patients. Accumulating evidence indicates that non-coding RNAs (ncRNAs) are involved in the pathogenesis of glucocorticoid-induced growth retardation (GIGR), but the roles of specific ncRNAs in growth remain largely unknown. Methods In this study, 2-week-old male Sprague-Dawley rats had been treated with 2 mg/kg/d of dexamethasone for 7 or 14 days, after which the growth plate tissues were collected for high-throughput RNA sequencing to identify differentially expressed mRNAs, lncRNAs, circRNAs, and miRNAs in GIGR rats. Results Transcriptomic analysis identified 1,718 mRNAs, 896 lncRNAs, 60 circRNAs, and 72 miRNAs with different expression levels in the 7d group. In the 14d group, 1,515 mRNAs, 880 lncRNAs, 46 circRNAs, and 55 miRNAs with differential expression were identified. Four mRNAs and four miRNAs that may be closely associated with the development of GIGR were further validated by real-time quantitative fluorescence PCR. Function enrichment analysis indicated that the PI3K-Akt signaling pathway, NF-kappa B signaling pathway, and TGF- β signaling pathway participated in the development of the GIGR. Moreover, the constructed ceRNA networks suggested that several miRNAs (including miR-140-3p and miR-127-3p) might play an important role in the pathogenesis of GIGR. Conclusions These results provide new insights and important clues for exploring the molecular mechanisms underlying GIGR.

Introduction The frequency of celiac disease autoantibody (CDAb) positivity in type 1 diabetes (T1D) has increased due to unclear mechanisms, including autoimmune injury. Circular ribonucleic acids (circRNAs) participate in autoimmune diseases, but the roles of circRNAs in T1D with CDAbs are currently unknown. This study aimed to determine the frequency of CDAbs in Chinese children with T1D and describe the relationship between CDAbs and circRNAs. Materials and methods Eighty patients diagnosed with T1D were screened for CDAbs and CD-predisposing genes, and circRNAs in peripheral blood mononuclear cells (PBMCs) were collected from 47 patients. The Gene Expression Omnibus (GEO) database was searched for candidate circRNAs in related studies on T1D PBMCs. Data on clinical characteristics (i.e., blood glucose control, residual islet function, and daily insulin dosage) and immunophenotypes (i.e., islet autoantibodies and immune cell subsets) were collected. Results In total, 35.0% of patients were positive for CDAbs. CD-predisposing genes accounted for 52.5% of the genes, and no significant difference in frequency was found between the CDAb-positive (CDAb+) and CDAb-negative (CDAb–) groups. In addition, among the differentially expressed circRNAs from the GEO database, five highly conserved circRNAs homologous to humans and mice were screened, and only the expression of hsa_circ_0004564 in the CDAb+ group significantly decreased (CDAb+ vs. CDAb–:1.72 ± 1.92 vs. 11.12 ± 8.59, p = 6.0 × 10–6), while the expression of hsa_circ_0004564 was upregulated in the general T1D population. Moreover, its parental gene RAPH1 was significantly upregulated (CDAb+ vs. CDAb–:1.26 ± 0.99 vs. 0.61 ± 0.46, p = 0.011). Importantly, the positive correlation between hsa_circ_0004564 and CD3+ cells was validated in children with T1D after adjustments for CDAbs (p = 0.029), while there were no correlations between hsa_circ_0004564 and clinical characteristics or other immune cell subsets (i.e., CD4+ T cells, CD8+ T cells, and natural killer cells). Conclusion This study highlights the importance of screening for CD in Chinese children with T1D, considering the high prevalence of CDAb positivity and CD-predisposing genes. The profile of candidate circRNAs in children with T1D with CDAbs was different from that in previous reports on general T1D patients from the GEO database. Moreover, hsa_circ_0004564 and its parental gene RAPH1 may be new targets for studying immune mechanisms in children with T1D and CD.

Objective: To investigate the gut microbiota distribution and antibiotic resistant genes (ARGs) carrying- status in the girls with precocious puberty (PP). Methods: A total of 29 girls were enrolled in the study, including 21 girls with precocious puberty (PP) [11 girls with central precocious puberty (CPP group), 10 girls with premature thelarche (PT group)], and 8 age-matched healthy girls (NC group). The fecal samples were analyzed to explore difference in composition of gut microbiota and ARGs numbers between the PP (CPP+PT) and NC groups using shotgun metagenomic sequencing. Results: The composition and abundance of gut microbiota in the PP girls were different from the NC girls. The relative abundances of top three gut microbiota in CPP, PT and NC girls were 50.03%, 37.73% and 67.61% for Firmicutes, 33.00%, 43.26% and 10.32% for Bacteroidetes, and 4.26%, 4.22% and 11.16% for Actinobacteria. Compared with the NC girls, the PP girls had a significantly higher abundance of Bacteroidetes (P=0.034) and much lower abundance of Firmicutes (P=0.006) and Actinobacteria (P<0.000 1). It revealed that there were 257, 273 and 240 species of ARGs identified in the CPP, PT and NC girls, respectively. The PP girls had more ARGs types and higher abundance of tetracyclines and macrolide ARGs than the NC girls. Conclusions: Compared with the NC girls, the PP girls have a different distribution of gut microbiota and more species of ARGs enriching in tetracyclines and macrolides. It indicates that the dietary and environmental antibiotic exposure may influence the gut microbiota distribution in children, which may be associated with the pathogenesis of PP.

Background The gut microbiome is important for host nutrition and metabolism. Whether the gut microbiome under normal diet regulate human height remains to be addressed. Our study explored the possible relationship between gut microbiota, its metabolic products and the pathogenesis of idiopathic short stature disease (ISS) by comparing the gut microbiota between children with ISS and of normal height, and also the short-chain fatty acids (SCFAs) produced by the gut microbiota. Methods The subjects of this study were 32 prepubescent children aged 4-8 years. The fecal microbial structure of the subjects was analyzed by 16S rRNA high-throughput sequencing technology. The concentrations of SCFAs in feces were determined by gas chromatography-mass spectrometry. Results The richness of gut microbiota in ISS group was decreased, and the composition of gut microbiota was significantly different between ISS group and control group. The relative abundance of nine species including family Ruminococcaceae and genera Faecalibacterium and Eubacterium , in ISS group was significantly lower than that in control group (P<0.05). The relative abundance of 10 species, such as those belonging to genus Parabacteroides and genus Clostridium , in ISS group was significantly higher than that in control group (P<0.05). The concentration of total SCFAs and butyrate in ISS group was significantly lower than that in control group. The correlation analysis among different species, clinical indicators, and SCFAs showed that the relative abundance of family Ruminococcaceae and genera Faecalibacterium and Eubacterium was positively correlated with the standard deviation score of height. Furthermore, the concentrations of total SCFAs and butyrate were positively correlated with serum insulin-like growth factor 1 (IGF-1)-SDS. Disease prediction model constructed based on the bacteria who abundance differed between healthy children and ISS children exhibited high diagnostic value (AUC: 0.88). Conclusions The composition of gut microbiota and the change in its metabolite levels may be related to ISS pathogenesis. Strains with increased or decreased specificity could be used as biomarkers to diagnose ISS.

Bisphenol A (BPA) is ubiquitous in the environment and its adverse effects on precocious puberty have been reported. But its mechanism is not clear. In the present study, the potential effects of BPA on endocrine functions of hypothalamus, especially in the arcuate (ARC) nucleus and anteroventral periventricular (AVPe) nucleus, were studied from postnatal day 15 (PND15) to PND35 in female Sprague-Dawley (SD) rats. Neonatal rats were exposed to 0.5 mg.kg-1.day-1 BPA or corn oil vehicle from PND1 to PND14 via intramuscular injection. From PND20 to PND 25, BPA caused enrichment of H3K4me2 and H3K4me3 at Kiss1 promoter, concurrent with elevated gene expressions of Kiss1 and GnRH1 in ARC and strikingly increased serum E2 levels in BPA group on PND25. Until PND30, BPA induced obviously overexpression of Kiss1 and GnRH1 in AVPe nucleus. Subsequently, the vagina opening and first ovulation had occurred earlier in rats with BPA exposure in respect to vehicle by PND35. In this study, it is suggested that the effects of BPA on precocious puberty may be due to its action to activate Kiss1 gene in ARC during the juvenile period (from PND20 to PND25) firstly, subsequently to evoke the AVPe neurons, resulting in precocious puberty in the end.